Hormonal Determinants and Disorders of Peak Bone Mass in Children1

PEAK BONE MASS can be defined as the maximal bone mineral density that is accrued during growth and development plus subsequent consolidation that continues during early adulthood (1). The precise age at which peak bone mineral density is acquired is still unknown and may be site dependent. It is generally accepted that maximal bone density is present during the third to fourth decade, but this assumption is based upon data derived from studies using densitometry techniques that are less precise than newer methods. Normative data are derived primarily from cross-sectional studies of adolescents and young adults, such as cohorts of the National Health and Nutrition Examination Survey (NHANES). Differences in absolute density depend on the various techniques used for assessing bone density [i.e. single photon absorptiometry, dual energy x-ray absorptiometry (DEXA), quantitative computed tomography (QCT)] and differences using the same method among different machines, emphasizing the importance of methodology, including the type of machine used when referencing normative databases. There are also ethnic differences in bone density, with blacks reported as having higher bone density than whites. There are gender differences in bone density during childhood and adolescence due to differences in the timing of growth and puberty, resulting in females reaching peak bone mass earlier than males, although bone density values at peak bone mass are similar between the sexes. An individual’s height, bone size, and skeletal age may all impact bone density values, particularly in growing children and adolescents. These variables should be considered when assessing the normality of an individual’s bone density, but unfortunately current reference data do not include information on these variables. More recent investigations have suggested that peak bone mass may be attained as early as late adolescence in the hip and spine (1). In healthy adolescents, bone mass increases throughout childhood, with maximal bone mass accrual occurring in early to midpuberty and slowing in late puberty (2–5). However, most published studies are cross-sectional and do not include individuals in sufficient numbers encompassing the entire age span of interest (i.e. teens to fourth decade) followed prospectively to definitively determine the age at which peak bone mass is attained. Longitudinal data from healthy girls demonstrate that the gain in bone mass is most pronounced between 11–14 yr of age and falls significantly after 16 yr of age and/or 2 yr after menarche, as shown in Fig. 1 (4, 5). These data suggest that there is a critical window in time to maximize bone density in early and midadolescence, and the majority of bone mass will accumulate by late adolescence. It has been shown in adult patients that each sd reduction in bone density is associated with a doubling of fracture risk. In children, as in adults, fracture rates have also been shown to be higher in individuals with a lower bone mineral content (6). Because an individual’s bone density is determined by peak bone density and the degree of later bone loss, an understanding of the factors responsible for maximizing peak bone mass is critical for preventing fractures in later life. In this review, the factors that influence the attainment of peak bone mass, particularly hormonal determinants and disorders, will be considered. Fig. 1. Gain in bone mass during adolescence. Yearly increase in spine bone mineral content (L2-L4) during adolescence in females (○) and males (•). (Reprinted with permission from The Journal of Clinical Endocrinology & Metabolism, 75:1062, 1992. Copyright © 1992 The Endocrine Society. All rights reserved.) Fig. 1. Gain in bone mass during adolescence. Yearly increase in spine bone mineral content (L2-L4) during adolescence in females (○) and males (•). (Reprinted with permission from The Journal of Clinical Endocrinology & Metabolism, 75:1062, 1992. Copyright © 1992 The Endocrine Society. All rights reserved.) There are important genetic determinants of bone density, as suggested by studies of twins and families (7–9), and the specific inherited factors involved are under investigation. Polymorphisms in the gene encoding the 1,25-dihydroxyvitamin D receptor may in part underlie genetic variation in bone mass (10–12). Studies examining the relationship between vitamin D receptor (VDR) polymorphisms and bone density have provided conflicting results, and a meta-analysis of studies in adults suggest that the VDR genotype makes a small contribution to observed bone density (11). In contrast, in a genetically homogeneous population of children, Sainz et al. reported that VDR polymorphisms accounted for a significant (>1 sd) difference in femoral and vertebral bone density between the homozygous recessive (aa, bb) and the dominant (AA, BB) genotypes (12). These data suggest that genotype may be of greater importance in predicting bone density early in life before age- and gonadal steroid-related factors affect bone mass. Studies in adults have suggested that calcium intake may be related to VDR genotype and bone density (13, 14). Similarly, in a study of prepubertal girls, dietary calcium intake correlated with change in bone density in those with homozygous dominant and heterozygous (BB and Bb) genotypes, but not in those subjects with the homozygous recessive (bb) genotype (15). These data suggest that VDR genotyping may be one factor determining the variation in bone density in children and could potentially be helpful in predicting benefits from calcium supplementation. Several other genetic loci that may play an important role in peak bone mass accrual are under investigation. A polymorphism in the Sp1 binding site of the collagen type 1 α1 gene (COLIA1) is one such candidate gene. This polymorphism is associated with decreased spinal bone density in prepubertal children with heterozygous (s) and homozygous recessive genotypes compared with the dominant (S) genotype, similar to findings in adult patients (16). The insulin-like growth factor I (IGF-I) gene is another important candidate due to its significant effects as a bone trophic although its role in peak bone mass has not been The important role of in and bone and density that receptor gene polymorphisms may also influence bone The site of the receptor gene has been to be related to bone density in studies of and young a growing of candidate have been that may be important determinants of peak bone mass. studies in with will be critical in assessing the impact of these factors on peak bone mass. The of in patients with development the critical impact of on bone mineral patients with have resulting from bone mineral accrual during puberty and/or bone after puberty as shown in Fig. 2 with a of of puberty have been reported to have decreased bone mass although data are conflicting are in growth in males and females and are to the effects of in bone However, to be the important involved in skeletal and although is unknown on bone by other of bone growth There are of patients with receptor resulting in these subjects have a that and However, these patients have and skeletal in adulthood of a with with in in bone density and of skeletal the critical role of in skeletal and Fig. In young a of fractures has been reported in particularly in those with late age of and of as shown in Fig. In adolescents, lower bone density is in teens compared with those with but the in bone density is generally not significant when bone density is for These data suggest that including growth and gonadal may be determinants of bone particularly in the of can to et al. that one third of females from during adolescence have with have during adolescence have lower spinal bone density than those with in adulthood These data are with the that there may be a window in time during adolescence in which maximal bone mass gonadal during this time will have a impact on adult bone mass. Fig. bone density in bone density compared with age in with with patients with The the spinal bone density in adult the sd from the The the fracture (Reprinted with permission from of Copyright © of Fig. bone density in bone density compared with age in with with patients with The the spinal bone density in adult the sd from the The the fracture (Reprinted with permission from of Copyright © of bone density in a with during The increase from values is shown for the at and (Reprinted with permission from Journal of Copyright © Society. All rights reserved.) bone density in a with during The increase from values is shown for the at and (Reprinted with permission from Journal of Copyright © Society. All rights reserved.) between age at and the of young with fractures and (Reprinted with permission from Journal of Copyright © Society. All rights reserved.) between age at and the of young with fractures and (Reprinted with permission from Journal of Copyright © Society. All rights reserved.) of and increase during puberty, by of of the on bone is in an and as a bone trophic that bone growth and bone by collagen and bone growth in children, bone density and of bone are significantly and with patients with have bone mass compared with patients during adolescence may to in is a of bone density in children and adolescents. Studies in healthy and children and adolescents demonstrate that mass with and bone mineral content with are also to determine the impact of these factors on bone In adolescents with such as the relationship between mass and bone density is not present that factors In patients there is an in bone with bone with in with bone density are in these due to effects of in to gene with bone in girls with has been to with of intake has been shown to with bone density in healthy children and adolescents. 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Fig. in bone density in children with and for bone age in children with the of reference (Reprinted with permission from The Journal of Clinical Endocrinology & Metabolism, Copyright © The Endocrine Society. All rights reserved.) Fig. in bone density in children with and for bone age in children with the of reference (Reprinted with permission from The Journal of Clinical Endocrinology & Metabolism, Copyright © The Endocrine Society. All rights reserved.) with may have bone mass due to the of on bone and the The of and vertebral in a prepubertal with that is to the of this in children, data on bone density are In the published of patients with patients yr bone density at in and one a fracture at The patients in densitometry to which but after and sd) in a with during adolescence. bone than 2 yr of bone density but compared with that in These data suggest that peak bone mass is a of in childhood and and to the of hormonal other to bone mass in this have not been bone mineral density in adult patients with is data on the effects of on peak bone mass are A study of girls with yr significantly and spinal bone density at compared with healthy girls for age and The bone density in girls in with bone as by However, bone not correlated with bone density and with in these bone density and bone significantly different from values at and of in patients These data suggest that effects bone and bone density in but that the effects can be with and are to affect peak bone mass in 1 There are conflicting data bone density is a of type 1 The majority of studies in adults demonstrate of and which is generally correlated with the of and of and the is in patients with other of an fracture has not been in this fractures have been reported in patients with and in those to be in adulthood that the bone density in adult patients may from a reduction in peak bone mass. 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All rights reserved.) bone from bone in girls with of bone in subjects with and for subjects bone (Reprinted with permission from The Journal of Clinical Endocrinology & Metabolism, Copyright © The Endocrine Society. 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